Peroxisome proliferators (PP) are a potential human health hazard because of their ability to induce hepatocellular adenomas in sensitive rodent species and the widespread exposure of human populations to PP. The mechanism of PP-induced hepatocellular adenomas has been attributed to increased peroxisome proliferation or hepatocyte proliferation, although attempts to accurately predict tumor incidences from these end points have been largely unsuccessful. Increased hepatocyte proliferation plays a key role in converting preneoplastic foci to adenomas. Hepatocyte proliferation has been recently shown to be dependent on expression of PPARalpha, the central mediator of PP effects and tumor necrosis factor alpha (TNFalpha), a hepatocyte mitogen. The overall goal of this proposal is to identify key growth regulatory genes that respond to PP and act as indicators of tumorigenic potential in rodents. The use of the NTP tissues is crucial to accomplish this goal. This proposal will address the hypothesis that (1) PP exposure leads to altered expression of growth regulatory genes by a PPARalpha- and TNF- dependent mechanism, (2) altered expression of these genes is accentuated in PP-induced tumors and (3) the extent of expression alteration of the genes is a useful predictor of hepatocyte proliferation and subsequent appearance of hepatocellular adenomas. This hypothesis will be tested in two specific aims. Specific Aim 1. Identification of PP-dependent cell proliferation genes. Genes will be identified in a novel mouse model in which hepatocyte proliferation can be uncoupled from peroxisome proliferation using high density cDNA arrays. Altered genes specifically linked to hepatocyte proliferation will be tested to determine if PP regulation is PPARalpha-dependent and whether altered expression is accentuated in PP-induced tumors. Specific Aim 2. Correlation of growth regulatory gene expression with hepatocyte proliferation and tumorgenicity. Expression of the growth regulatory genes will be correlated to previously measured levels of hepatocyte proliferation in NTP tissues derived from responsive and relative insensitive species and to historical databases of tumor incidences. The data generated in this proposal will (1) lead to a greater understanding of the mechanism of PP-induced hepatocyte proliferation and (2) identify genes which are the best predictors of tumor induction by PP. These data will allow comparisons to be made between responsive species and humans to determine if humans possess the same mechanism and if so, whether the mechanism is induced after exposure to PP.